The objectives of these studies are to delineate the cellular mechanisms involved in the physiologic regulation of cyclic GMP (cGMP) metabolism in kidney and to investigate the possible role of cGMP in control of selected aspects of renal intermediary metabolism. In previous studies, the modulation of basal cGMP and expression of the actions of many endogenous homoral agonists, such as cholinergic stimuli, bradykinin and histamine to increase cGMP in kidney were found to be dependent upon the presence of both extracelluar Ca 2 ion and molecular O2. The possibility that these Ca 2 ion and O2 dependent processes involved Ca 2 ion stimulation of arachidonate release from tissue lipid pools and the subsequent oxygenation of arachidonate to endoperoxide or hydroperoxide activators of the guanylate cyclase system was examined. Increases in both renal cortical and medullary cGMP induced by Ca 2 ion with or without the divalent cation ionophor A23187 were correlated temporally with release of (14C) arachidonate from tissue lipid polls. In cortex the action of Ca 2 ion, Ca 2 ion plus A23187, carbamylcholine and exogenous arachidonate to increase cGMP were blocked by O2 exlusion and by the arachidonate analogue TYA, but not by cyclo-oxygenase inhibitors. Thus, in this tissue oxygenation of arachidonate to prostaglandin metabolites is not implicated as an important determinant of cGMP control. By contrast, in inner medulla indomethacin and naproxen block cGMP responses to Ca 2 ion, A23187, carbamylcholine and exogenous arachidonate. Moreover, increases in cGMP under various conditions of incubation are correlated with stimulation of prostaglandin sysnthesis in inner medulla. Thus, in this tissue control of cGMP appears to be closely linked to prostaglandin synthesis. In inner medulla, trifluoperazine, an inhibitor of the actions of the calcium-calmodulin complex was also found to suppress prostaglandin synthesis and cGMP in response to A23187. Studies are currently in progress exploring the role of calmodulin in Ca 2 ion dependent regulation of cGMP in kidney.